The present invention relates generally to apparatus and methods for mixing small volumes of materials and, in particular, to such apparatus and methods as used in a parallel reactor in which chemical reactions are conducted simultaneously using small volumes of reaction materials to efficiently and economically screen large libraries of chemical materials in a combinatorial (i.e., high-throughput) process.
In a parallel reaction procedure, small volumes of reaction materials (e.g., liquids) are placed in an array of reaction vessels, each having a volume which is preferably less than about 100 ml, and more preferably less than about 30 ml., the vessels being contained within one or more reaction blocks of a reactor system. The contents of each vessel (which may include a mixture of liquids, solids and/or gases) are mixed in an effort to obtain a substantially homogeneous solution. Various mechanisms have been used for such mixing, including but not limited to high-speed shaft-driven rotational stirrers, magnetic flea stirring bars, orbital shakers, and vibratory devices. However, due at least in part to the relatively small sizes of the vessels and mixing implements, efficient mixing has been difficult to achieve. There is a need, therefore, for an improved apparatus and method for achieving effective mixing in a parallel reactor and, more broadly, in other applications involving mixing materials in small vessels.
For details regarding the construction and operation of prior parallel reactors using high-speed stirring mechanisms, reference may be made to co-owned International Application No. PCT/US 99/18358, filed Aug. 12, 1999 by Turner et al., entitled Parallel Reactor with Internal Sensing and Method of Using Same, published Feb. 24, 2000 (International Publication No. WO 00/09255), co-owned provisional U.S. application Ser. No. 60/264,489, filed Jan. 26, 2001 (now abandoned but forming a basis for pending U.S. application Ser. No. 10/060,075 filed on Jan. 28, 2002, U.S. Publication No. 2002-0106813), by Jonah R. Troth et al, entitled Apparatus and Methods for Parallel Processing of Multiple Reaction Mixtures, and co-owned pending U.S. application Ser. Nos. 60/209,142 filed Jun. 3, 2000 (now abandoned but forming a basis for pending U.S. application Ser. No. 09/873,176 filed on Jun. 1, 2001) by Safir et al., titled Parallel SemiContinuous or Continuous Stirred Reactors, Ser. No. 60/255,716 filed Dec. 14, 2000 (now abandoned but forming a basis for pending PCT application Ser. No. 01/17921 filed on Jun. 1, 2001, International Publication No. WO 01/93998A2) by Safir et al., titled Parallel SemiContinuous or Continuous Stirred Reactors, and Ser. No. 09/873,176, filed Jun. 1, 2001, by Nielsen et al., titled Parallel SemiContinuous or Continuous Reactors. These applications are incorporated herein by reference for all purposes.
Among the several objects of this invention may be noted the provision of improved apparatus and methods for mixing small volumes of fluids, such as small volumes of liquid reaction materials in parallel research reactors; the provision of such apparatus and methods which achieve a more homogeneous mixture of such materials; and the provision of a vessel and impeller designed to achieve effective mixing of volumes of material preferably less than about 20 ml, and more preferably no more than about 10 ml.
In general, a method of the present invention method involves mixing reaction components in a parallel reactor. The method comprises positioning a plurality of removable vessels in the reactor, each vessel as so positioned having a closed bottom, a side wall extending up from the bottom, an open top, and an overall capacity. Reaction components to be mixed are delivered to each of the vessels to fill each vessel up to a fill level spaced above the bottom of the vessel and below the top of the vessel, the reaction components thus occupying a fill volume of the vessel less than said overall capacity. An impeller in each vessel is rotated to mix the reaction components in the vessel, each impeller comprising a rotary shaft and at least one blade on the shaft positioned in said fill volume. The at least one blade of each impeller is dimensioned such that one rotation of the impeller causes the at least one blade to sweep out a sweep volume representing about 20%-50% of said fill volume of a respective vessel.
Another aspect of the present invention is directed to mixing apparatus for use in a parallel reactor. The apparatus comprises a vessel for containing reaction components to be mixed, the vessel having a closed bottom, a side wall extending up from the bottom, and an open top. The vessel has an overall capacity of less than about 50 ml and a height to inside diameter ratio of less than 5.0. The apparatus further comprises an impeller for mixing the reaction components in the vessel. The impeller comprises a rotary shaft adapted to be positioned in the vessel, and at least one blade on the shaft having an upper edge, a lower edge and opposite side edges, a width between the side edges at least 60% of the diameter of said vessel, and a blade area as viewed in vertical broadside profile sufficient to sweep out a sweep volume at least 10% of the overall volume of the vessel during one revolution of the blade in the vessel.
The present invention is also directed to a parallel reactor comprising a plurality of reactor vessels for containing reaction components, each vessel having a closed bottom, a side wall extending up from the bottom defining an overall capacity of said vessel of less than 50 ml and an open top, and a central vertical axis. The vessel has a height to inside diameter ratio of about 5.0 or less. The reactor also includes a plurality of impellers, one for each vessel, for mixing the reaction components. Each impeller comprises a rotary shaft adapted to extend down into the vessel and having an axis of rotation, and at least one blade on the shaft immersible in the reaction components in the vessel for mixing the components upon rotation of the shaft. The at least one blade has a blade area sufficient to sweep out a sweep volume at least 10% of the overall volume of the vessel during one revolution of the blade in the vessel.
This invention is also directed to an impeller comprising a rotary shaft having a longitudinal axis, and at least one substantially flat longitudinal blade on the shaft adapted to be positioned in the reaction components in the vessel for mixing the components upon rotation of the shaft. The blade has a body and a narrow longitudinal extension projecting from the body.
In yet another aspect, a method of this invention for mixing a small volume of liquid comprises placing no more than 10 ml of a combination of liquid and/or solid materials into a vessel so that the materials occupy a fill volume of the vessel, the vessel having a closed bottom, a side wall and an open top. An impeller is rotated in the vessel to mix the combination of materials. The impeller has a rotary shaft and at least one blade on the shaft positioned in the materials during rotation of the impeller. The at least one blade has a blade area dimensioned such that one rotation of the impeller sweeps out a volume corresponding to at least 20% of said fill volume.
Another method of the present invention for mixing a small volume of material comprises placing a combination of liquid and/or solid materials into a vessel having a closed bottom, a side wall, an open top and an overall capacity of less than 50 ml. An impeller is rotated in the vessel to mix the combination of materials. The impeller has a rotary shaft and at least one blade on the shaft positioned in the materials during rotation of the impeller. The at least one blade has a blade area dimensioned such that one rotation of the impeller sweeps out a volume corresponding to at least about 10% of said overall capacity of the fill vessel.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.